1. Field of the Invention
The present invention relates to pharmaceutical products which are particularly useful in the treatment of hyperphosphateaemia at chronic uraemia, as well as for the prophylaxis of kidney stones, particularly oxalate stones, to calcium mixed salts of polymeric, natural and chemically modified anionic carboxylic acids and/or esters of sulfuric acid, to methods for their preparation, and to methods of their use.
At the present time, there are approximately 14.000 patients in the Federal Republic of Germany which suffer from chronic uraemia, and the tendency is increasing. These patients have to undergo a blood purification or cleansing treatment for three to six hours three times per week. Such known treatments include haemodialysis or haemofiltration, and peritoneal dialysis, respectively. These treatments aim to remove uraemic toxins, such as, for example, urea, uric acid, creatinine and the like, as well as phosphate, from the organism, i.e. from the blood. Despite of dietary measures, the phosphate level is still too high in most patients even after the blood purification. The hyperphosphateaemia represents a substantial factor in the pathogenesis of the secondary hyperparathyrodism with development of the renal osteopathy under chronic dialysis treatment. The causes of this are the binding of phosphate to certain proteins and the intestinal resorption of phosphate from food and of phosphate from the fluid of the gall. Accordingly, almost all uraemia patients have to rely on additional medication to lower the phosphate level to the normal range.
2. Description of the Prior Art
Aluminium hydroxides were predominantly used in the last few years for the intestinal binding of phosphate in such patients. These include, for example, ALUDROX.RTM., ANTIPHOSPHAT.RTM., ALUCAP.RTM., and PHOSPHONORM.RTM.. These were applied in amounts of up to 10 g and more per day (M. B. Kaye, Arch. Intern. Med., 124,646 (1969)). A further aluminium-containing salt for the reduction of the phosphate resorption is described in DE-OS No. 2 618 083 (DE-OS=German patent publication).
However, these known products for the binding of phosphate have disadvantages. Through partial dissolution of the aluminium hydroxide, Al (OH).sub.3, in the stomach to Al (OH) Cl.sub.2 and AlCl.sub.3, Al.sup.3+ is liberated, and this is partially resorbed in the stomach and the upper small intestine, enters, via the blood, into the bone substance as well as other parts of the body (liver, erythrocytes, etc.), and, in the case of many years of exposure thereto, causes considerable damage (compare, for example, haemodialysis-encephalopathy, osteomalacia with tendency to spontaneous fractures, hypercalcaemia, decreasing of muscle strength) (A. C. Alfrey, J. M. Mishell, J. Burks, S. R. Contiguglia, H. Rudolph, E. Lewin, J. H. Holmes, Trans. Amer. Soc. Artif. Int. Org., 18, 257 (1972); A. C. Alfrey, G. R. Le Gendere, W. D. Kaehny, New. Eng. J. Med., 294, 184 (1976); A. M. Pierides, W. G. Edwards jr., U. X. Cullum jr., J. T. Mc Call, H. A. Ellis, Kidney Intern., 18, 115, (1980)). According to EDTA-statistics 10 to 12% of the dialysis patients die annually with cerebral incidents, more than a few due to a dialysis-encephalopathy (H. Pogglitsch, Nieren-u. Hochdruck-krankheiten (Kidney and High Pressure Diseases), 10, 210 (1981)).
The lowering of the average dose of aluminium hydroxide to a third thereof caused a significant lowering of the concentrations of plasma-aluminium. Thus, from a medicinal point of view it appears urgently adviseable to discontinue the presently used aluminium preparations for the binding of phosphate. However, till now no suitable therapeutical replacement has been available.
From the food there are resorbed, per day, approx. 200 g water and 2.7 g phosphate in the intestine. From digestive fluids are added a further 8.000 g water and 0.3 g phosphate. The resorption of Ca.sup.2+ and Fe.sup.2+ occurs in the upper small intestine and the middle intestine, respectively.
Because of disturbances of the functioning of the kidneys during chronic uraemia, the following amounts of substances have to be removed from the blood of a patient, per treatment, generally three times per week, among others: 3 to 6 g phosphate and 1.500 to 2.000 g water.
The manifestation of uraemia includes furthermore a deficiency of Ca.sup.2+ and Fe.sup.2+ ions. Thus, such a patient should be given approx. 1 g calcium and 100 to 200 mg Fe.sup.2+, per day. The latter is only resorbed to 10 to 15%. Of disadvantage is a momentary excess dose during the short period of administering the entire amount, as well as a related incompatibility (danger of hypercalcaemia). Furthermore, most of the patients who suffer from chronic uraemia also suffer from sluggishness of the bowel and constipation of the bowel, respectively. Such patients frequently exhibit a deficiency in trace elements.
A composition for raising the calcium content of blood in animals is described in DE-OS No. 2 505 755 (DE-OS=German patent publication), as well as a method of preparing such composition. The composition is comprised of an aqueous mixture of calcium chloride and a gel-forming polymer. As polymers, the polyvinyl alcohols or polyethylene glycols, acrylic acid polymer and carboxymethylcellulose, are described in the prior art patent publication. These compositions can not be used in humans, because until now it is not proven that they per se, their monomers, or their metabolism products, respectively, are not toxic.
Kidney stones, particularly oxalate stones, can be formed, among others, thereby that through the intake of food which is rich in oxalate, and by resorption of the oxalate in the intestine during urine preparation, there arise high concentrations of oxalate in the kidney, and the solubility product of the calcium oxalate is exceeded. Similar considerations apply in the formation of calcium-phosphate stones.